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Clinical genetic care in diseases predisposing to sudden cardiac death
van Langen, I.M.
Publication date2005
Link to publication
Citation for published version (APA):van Langen, I. M. (2005). Clinical genetic care in diseases predisposing to sudden cardiacdeath.
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Download date:10 Apr 2021
Chapter
An extended family suddenly confronted with a life
threathening hereditary arrhythmia
KSWH Hendriks, IM van Langen, JP van Tintelen, FJM Grosfeld,
AAM Wilde and HFJ ten Kroode
Neth Heart J 2005; 13: 295-9
CHAPTER 7
Abstract
Objective:This exploratory study serves to illustrate the psychological impact on an extended
family in the process of genetic counselling and testing for a potentially life threatening
arrhythmia, the Long QT Syndrome (LQTS).
Method: All members of the third generation and their partners (n=11) were interviewed, the
mutation carriers with partners twice. In addition they completed measures for anxiety and
depression three times in 18 months.
Results: During the interviews these family members emphasised the damaged solidarity
when the family is divided in carriers and non-carriers of a mutation in a LQTS predisposing
gene. This demonstrates one way in which a family can react to the reality of being at risk for
a potentially severe disease. Rewriting the family history and mourning for earlier death seem
other ways to deal with this. The distress scores, especially of the women, were moderate to
clinically high, not because of their own chance to get an arrhythmia but more due to their
children's risk.
Conclusion: Mothers need educational even more than emotional support, because the life
style of their carrier children is in need of radical change. The setting of a combined outpatient
cardiogenetic clinic with a medical and psychosocial staff foresees efficiently in such needs.
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Introduction
Long QT syndrome
The long QT syndrome (LQTS), or Romano Ward syndrome, is a heritable cardiac disorder
characterised by prolongation of the QT-interval on the electrocardiogram (ECG). The
mode of inheritance is autosomal dominant, its expression is variable and its penetrance is
decreased (with about 50% of carriers never getting symptoms). Carriers of a mutation in one
of the six known LQTS-genes are at risk for ventricular cardiac arrhythmias causing dizziness,
fainting and sudden death, often (long) before the age of 40 [1-6].These arrhythmias can be
triggered by certain gene-specific circumstances, especially physical exertion and emotions
[7]. In LQTS type 2, caused by mutations in the chromosome 7-linked KCNH2 (former HERG)
gene, arousal and loud noises may also trigger symptoms [8]. Known mutation carriers of
LQTS types 1 and 2 (85% of the LQTS population) receive prophylactic treatment with 13-
blockers, which decreases the risk of sudden death substantially in the majority, provided
that they are used as prescribed [9,10]. In severe cases, the use of pacemakers or ICD's is
recommended [11]. Prophylaxis in asymptomatic mutation carriers is started from the age
at which symptoms can be expected to develop (dependent on the gene involved), usually
before the age often years.
In the Netherlands, it is for a decade that diagnostic DNA testing for LQTS has been possible.
for a decade now. If a mutation is detected in an index patient, the first-degree relatives are
actively approached by means of family letters, provided by a cardiogenetics team.These letters
inform relatives about the hereditary nature of the disease in their family and the possibility of
clinical investigation as well as DNA testing. Such a team consists of a cardiologist, a clinical
geneticist, a genetic counsellor and a psychosocial worker. It provides genetic counselling and
testing in a cardiogenetic outpatient clinic situated in an university hospital [12]. Approximately
50% of a carrier's relatives will also carry the mutation, which makes their treatment and
consequent predictive DNA testing in first degree relatives possible.
It is important to gain insight into the effects of mutation detection in an index patient
brings all about in his family. So we decided to follow in an exploratory study one of the first
Dutch families for whom DNA testing became available. This family study is part of a series of
systematic empirical studies determining what the psychological consequences are of genetic
counselling and testing for LQTS [13,14].
The family
The family lives in a new polder in The Netherlands; the parents were pioneer farmers on the
newly reclaimed land. Five girls and one boy were born; all the girls married and now have
children themselves (figure 1). Together with their husbands they form a close-knit extended
family, of which the ties became even stronger after the sudden death of both parents. The
mother (11:4) died in 1990 at the age 49 years due to a traffic accident.The setting sun was said
to have dazzled her and made her drive into the side of a truck. Seven years later the father
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C H A P T E R 7
(11:3) died of pneumonia at the age of 58 years while he also suffered from a rapidly progressive
dementia.
Methods The three carriers of the third generation and their partners were interviewed twice in three
years. Those with a normal ECG and without the gene mutation were interviewed once, as
well as their partners. Further information came from the regular visits of this family to the
cardiogenetics outpatient clinic in Amsterdam and from the social worker frequently in
touch with the third generation. At three different points in time they completed standard
measurement instruments on anxiety and depression (Impact of Event Scale, Spielberger State
Anxiety Inventory and Beck Depression Inventory).
fig. 1
I —0
0—0
D- D- -© I I ~
D—• 0 D- D- -©
IV • s ®
i E
i i O D
Legend
°/D •/• % !
a Female/male, no DNA tets, no LQTS complaints
- female/male mutation carrier LQTS2
= female /male non-carrier
tf <«>
= deceased
= index patient
• N relatives, sex unkown
= year of birth (in generation IV only the oldest + youngest because of privacy)
Results
It was in 1997 that the family became aware of LQTS. Two weeks after her maternity leave due
to the birth of a son (IV:6) and a few months after her father's death, the middle sister (lll:6)
collapsed on the parking lot at work. Luckily she was immediately resuscitated and in coma she
was transported to the hospital in coma.There a cardiologist found that she had suffered from
a ventricular fibrillation in the setting of a prolonged QT-interval. In the absence of potential
causal external factors he diagnosed congenital LQTS and discussed the possible hereditary
nature and its consequences with her husband. Both agreed that some of her blood should be
taken for genetic testing. This made her the index patient of her family.
As a farmer the patient's husband was familiar with the Mendelian laws of inheritance. By
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A N E X T E N D E D F A M I L Y W I T H A H E R E D I T A R Y A R R H Y T H M I A
asking questions, reading articles, and surfing on the internet he rapidly learned a lot more
about the disease. With this information he went to his wife's sisters and brother and informed
them about what was going on in their family and what would be wise to do. As a result within
a short time the sisters and brother presented themselves at the cardiogenetic outpatient clinic
in Amsterdam. Initially abnormal ECGs, suggestive for LQTS, were found in two sisters (111:2 and
111:9), both free of physical complaints. Alarmed, both immediately took their children to this
clinic where signs of LQTS were also found in the first two children (IV: 1 and IV2; then aged 9
and 7 years) of the oldest sister (111:2). At that moment (1997-8) ECGs of the other children of the
third generation did not display abnormalities.The cardiological examinations neither revealed
abnormalities in the other two sisters (111:4 and 111:11) nor in their brother (111:7). All consented to
have a blood sample stored until a mutation would be detected in the index patient.
The index patient regained consciousness ten days after the arrhythmia. She was treated
with a B-blocker and an ICD was implanted. She was moved from the hospital to a rehabilitation
centre because of serious impairments in speech and movement due to cerebral damage.
There she stayed for months. Initially she also had amnesia; e.g. she could not remember the
birth of her son and her father's death some weeks earlier. It was only little by little that these
functions partially recovered. Three years after the event she dared to become pregnant again
and subsequently gave birth to a daughter (IV:7). Until now the index patient has been free of
symptoms.
Solidarity
Those who received normal ECG-resuits did not feel relieved. Sister 111:4 was afraid that the
forthcoming DNA test results would divide the family in two separate groups: carriers and
non-carriers. It seemed as if she regretted not showing LQTS features. More or less angry she
said: 'The fact that the cardiogram demonstrates that I most likely don't have that gene makes me
unhappier than my two sisters for whom it seems quite sure that they are carriers. I'm not so glad
with that ECG, because now I cannot have the same feelings as they have... At home we were five
girls and one boy; we have always had an intense relationship with each other, and... I don't want
anything to change that!'
At that moment she preferred to be identified as a carrier as well because of the solidarity
she felt with her three probable carrier sisters. Her husband could not understand this. His
reaction ('Fine! Most likely you don't have it. Then our children are also free from it!') caused her
irritation. Less pronounced we found the same feelings and thoughts with her brother (111:7)
and the other unaffected sister (111:11).
Rewriting the family history
None of the sisters with a prolonged QTc nor their children had ever had physical complaints
suggesting cardiac arrhythmias.The mother (ll:4) on the other hand did have symptoms: she
had fainted frequently all her life. Nobody took this seriously; fainting seemed to be part of
her personality as if psychologically induced. It was thought that having six children within
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C H A P T E R 7
eight years and the harsh life of settlers in a new polder must have been an important cause of
this'behaviour'. Initially the deadly car incident of nearly ten years earlier was also explained by
such a faint, since some months before she had also driven from a bridge, without any injury.
After the family had learned about the hereditary nature of this arrhythmia the mother was
regarded as the person who'brought in'the disease. This resulted in 'rewriting' the collective
family history based on this new idea. Confusion arose when finally the ECGs from father as
well as mother were collected from the medical files in the archives of the regional hospital.
Mother's ECG appeared to be completely normal, while father's showed an obvious prolonged
QT-interval. This was not completely convincing, however, because father was using QT-
prolonging medication (anti-psychotics) at that time.
Distress: anxiety and worries
In the first interviews, just after the ECG, nearly all stated that the awareness of having a
familial predisposition for an arrhythmia would not cause them emotional burden. The
scores on the measurement instruments, however, contradicted these statements, for two
sisters (111:4 and 111:9) scored moderately and two (111:2 and 111:11) had a clinically high score
on the distress questionnaires, implicating the need for psychological help.The husband of
the eldest sister (111:1) was the only male with a somewhat higher score at that time, which is
understandable due to the alarming ECG results of two of his children. The distress scores at
both other measurements (just after DNA-test disclosure and 18 months later, respectively)
were somewhat lower, but remained above the cut-off score between normal and high
anxiety.The later scores of the eldest sister still showed an objective need for psychological
help for what she obviously had not asked for. She had only taken some sedatives for a short
time.
In the interviews we noticed that these sisters' high anxiety scores were not so much due
to their own health risks, but were mainly caused by the worries concerning the dangerous
situation in which some of their children were in. The worries of 111:2 were mainly connected
with her eldest child (IV: 1) who had developed into an active youngster and a talented footballer
scouted for a regional youth team. Stopping him was expected to damage his self-esteem to
such an extent that his parents had decided to let him play, seemingly a sensible decision
generating a lot of anxiety as well. This difficult decision brought his mother to admit that she
needed professional help: 'Not so much f or myself but for the problems I have with the upbringing
of my children who are healthy but seriously in danger of a deadly disease'.
A social worker provided it.The mother was advised to slowly direct her children's attention
to less competitive physical activities and to stimulate them in other pursuits in which they also
took pleasure. The eldest daughter (IV2) for instance enjoyed drawing and seemed talented,
but despite all encouragement she and her elder brother preferred competitive sports instead
of pursuing a quieter hobby. The help of the social worker facilitated emotional acceptance of
the parents of the own responsibilities of their children in these parts, and eventually led to less
anxiety, worry and depression on the part of their mother.
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Bad news
More than two years after her serious arrhythmia a pathogenic mutation was found in the
index patient, in the so-called 'human ether a-go-go related gene' (HERG- or KCNH2-gene),
responsible for LQTS type 2. After a careful family information meeting the third generation
decided that they wanted to be informed about their and their children's genetic status. They
were not only interested in knowing who the carriers and non-carriers were, but they also
wanted to be informed about each individual's risk of actually developing symptoms of the
disease.The DNA testing results, more than two years after the cardiological investigations, did
not only confirm the ECG-results of the sisters and their children but also revealed five other
carrier children, in the end all children of the three carrier sisters except one (IV:8) turned out
to be carriers.
There was still something else which they were concerned about. Based on his abnormal
ECG, the clinical geneticist and the cardiologist advised the family to inform the father's relatives
about the hereditary characteristics of LQTS; information leaflets were supplied to do so. At first
no one wanted to be a messenger of bad news, because all were anxious about the reactions
this news could provoke. The relationships within father's extended family were disintegrated
in such a way that this was thought to be very possible. However, the expected anger did not
follow. The distant family members were rather glad by the renewed contact as opposed to
upset by the bad news.
All father's seven brothers and sisters immediately came to the cardiogenetics outpatient
clinic. At first no one seemed to have a prolonged QT interval. DNA testing, however, revealed
that one of these brothers (11:1) was also a carrier. From a prophylactic point of view it was
very convenitent that he was already being treated with a B-blockade for hypertension. In that
period his eldest son, an airline captain of an airliner, developed an arrhythmia during take-off
and died a week before he would have come to the cardiogenetic outpatient clinic. His family
decided not to have postmortal DNA testing done. The relationships between both family
branches have lastingly been improved despite all bad news. The detection of the mutation
in the brother confirmed the diagnosis in the father of our index patient. Again the collective
family history had to be rewritten.
Renewed mourning
lll:9 was pregnant of her third child (IV:10) when her positive carrier status was disclosed.
She and her brother were less worried during interview and in the questionnaires both after the
ECG and the DNA-test outcome than the others; she seemed neither anxious about her own
risks nor was she worried about her children. Only because of her pregnancy had she stopped
running and playing competition volleyball. She did not know if she would practice this sports
again after delivery and argued: 'May be I will not have time for it: three kids and this farm we
recently moved /nfo.'Seemingly she did not want to relate her behavioural change to the reality
that she is someone with features of a serious disease; there was no matter of denying reality,
but rather an impressive decision not to let predictive medical and genetic findings with a
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probability character influence her life.
It was striking that, just like after receiving the normal ECG-results, the non-carriers did
not feel relieved with their DNA-test results. Anxiety and other unpleasant feelings hardly
decreased. All had the same explanation: it was not so much the hereditary disease and the
future but the past that caused their worries. For a while they had considered the death of
their mother from another perspective: not the dazzling by the evening sun but an arrhythmia
would have caused the accident. And now with father as the probable mutation carrier they
had to turn back this explanation again from arrhythmia to dazzling. Furthermore so much
had been happening: their beloved father died followed by the painful job of emptying and
selling the parental home, the index patient nearly died and had to stay in a rehabilitation
centre for months, having to care for a baby when not remembering giving birth, the mixture
of joy and great worries when the index patient became pregnant again, and the move of the
index patient and sister 111:9 to a new farm. At the time of the DNA-test disclosure all were still
mourning for their father's death - for which there had been no time earlier - and again for
that of their mother.
Discussion
Through this family's reactions - e.g. the postponed and renewed mourning for the loss of
both parents and the need to 'rewrite'family history twice - we noticed differences compared
to findings in studies among applicants for Huntington's Disease (HD), Multiple Endocrine
Neoplasia (MEN) and Hereditary Breast and Ovary Cancer (HBOC) [15,16,17]. Persons who
apply for DNA testing for these disorders most often have usually known for years about the
hereditary disease in their family and have also been aware of the extent of the impact. The
members of this LQTS-family on the other hand were completely surprised that a hereditary
arrhythmia runs in their family.
What seems particular for this family can be found in most LQTS families [14].The solidarity
and the fear of a family that they will be split up in carriers and non-carriers cause ambivalent
feelings in non-carriers: on the one hand the great relief that the gene mutation was not found
and that they and especially their children are no longer at risk, and on the other hand the
silent wish that the DNA-test nevertheless would reveal that they too are carriers of the familiar
LQTS mutation. This phenomenon corresponds with what Kessler et al. labelled as survivor's
guilt [18,19].
Nearly all LQTS families have grim experiences of family members who died totally
unexpected: a baby with sudden infant death syndrome, a child who could swim but still
drowned, a trained sportsman who died during a race. They know of relatives who suffer
from dizziness, syncopes or bed-wetting. Some were diagnosed with epilepsy and have been
treated with anti-epileptics. When such a family learns the real cause of these miseries a process
of rewriting the collective family history takes place, in which often renewed mourning for
deceased family members.
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Worry, anxiety and concern were most serious and even clinical in the carriers of this
family, not so much due to their carrier status but because of the risk for their children. Due to
their children's risk parents are faced with educational dilemmas. Parents feel responsible for
their children's life style and especially have to urge the child to regularly take its prescribed
prophylactic medication for even missing one dosage can provoke an arrhythmia.
This finding has been confirmed in another study of our group in which it was found that
the carrier status of the parent seemed of less influence on the level of distress than the carrier
status of the children [14]. We found that parents were more focussed on the well-being of their
children than on that of their own. This finding has also been reflected in studies addressing
the motivation for genetic testing for a variety of hereditary diseases. In these studies the well-
being of their children was one of the main reasons for parents to apply for genetic testing
[16,20-23].
Conclusion
The story of this family, combined with the results of the psychological measurements in LQTS
families, underline the needs of these families as being medical as well as psychological and
- because of their children - educational [14]. Especially mothers need educational support for
their children even more than psychological support for themselves; in particular they need
help to change their children's lifestyle. These needs can best be answered in the setting of a
combined outpatient cardiogenetic clinic, in which medical and psychosocial workers closely
collaborate in testing as well as follow-up.
Acknowledgements
We would like to thank family A. and Alma Schiphorst, social worker, for all the information
needed for this paper. We are grateful to Kathy Schlich-Bakker for her linguistic help. The study
was granted by the Netherlands Heart Foundation (grant 99.115). We acknowledge the Bohn
Stafleu van Loghem publishing group for permission to reproduce this article.
This study was approved by the Ethics committee of the University Medica Centre Utrecht.
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CHAPTER 7
References
1 Priori SG, Barhanin J, Hauer RN, Haverkamp W, Jongsma HJ, Kleber AG, McKenna WJ, Roden DM, Rudy Y, Schwartz PJ, Towbin JA, Wilde A.. Genetic and molecular basis of cardiac arrhythmias; impact on clinical management. Study group on the molecular basis of arrhythmias of the working group on arrhythmias of the European Society of Cardiology. Eur Heart J 1999;20(3):1 74-95.
2 Roden DM, Spooner PM Inherited long QT syndromes: a paradigm for understanding of arrhythmogenesis. J Cardiovasc Electrophysiol 1999;10(12):1664-83.
3 Chiang CE, Roden DM.The long QT syndromes: genetic basis and clinical implications. J Am Coll Cardiol 2000:36(1 ):1-12.
4 Wilde AA, van Langen IM. Van gen naar ziekte; ionkanaaleiwitten en het lange-QT-intervalsyndroom [From gene to disease; ion channel proteins and the long QT syndrome]. NedTijdschr Geneeskd 2000;144(46):2205-7.
5 Wang L. Congenital long QT syndrome: 50 years of electrophysiologic research from cell to bedside. Acta Cardiol 2003;58(2):133-8.
6 Chiang CE. Congenital and acquired long QT syndrome. Current concepts and management. Cardiol Rev 2004;12(4):222-34.
7 Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C, Denjoy I, Guicheney P, Breithardt G, Keating MT, Towbin JA, Beggs AH, Brink R Wilde AA, Toivonen L, Robinson JL, Timoth KW, Corfield V, Wattanasirichanigoon D, Corbett C, Haverkamp W, Schulze-Bahr E, Lehmann MH, Schwartz K, Coumel R Bloise R.. Genotype-phenotype correlations in the long-QT syndrome: gene specific triggers for life-threatening arrhythmias. Circulation 2001:103(1 ):89-95.
8 Wilde AA, Jongbloed RJ, Doevendans PA, Duren DR, Hauer RN, van Langen IM, van Tintelen JP, Smeets HJ, Meyer H, Geelen JL. Auditory stimuli as a trigger for arrhythmic events differentiate HERG-related (LQTS2) patients from KVLQT1 -related patients (LQTSl).J Am Coll Cardiol 1999;33(2):327-32.
9 ItohT, Kikuchi K, Odagawa YTakata S, Yano K, Okada S, Haneda S, Nakano O, Kawahara Y, Kasai H, Kakayama T, FukutomiT, Sakurade H, Shimizu A, Yazaki Y, Nagai R, Nakamura YTanakaT Correlation of genetic etiology with response tot beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome. J Hum Genet 2001 ;46(l):38-40.
10 Villain E, Denjoy I, Lupglazoff JM, Guicheney P, Hainque B, Lucet D, Bonnet D. Low incidence of cardiac events with beta-blocking therapy in children with long QTsyndrome. Eur Heart J 2004;2(16):1405-11.
11 Priori SG, Napolitano C, Schwartz PJ, Griiio M, Bloise R, Ronchetti E, Moncalvo C, Tulipani C, Veia A, Bottelli G, Nastoli J. Association of long QT syndrome loci and cardiac events among patients treated with beta-blockers. JAMA 2004;292(11):1341 -4.
12 Van Langen IM, Hofman N.Tan HL, Wilde AA. Family and population strategies for screening and counselling of inherited cardiac arrhythmias. Ann Med 2004;36 suppl 1:116-24.
13 Ten Kroode HFJ, van Langen IM, Hendriks KSWH, van Tintelen JP, Grosfeld FJM, Wilde AAM. Het lang-QT-intervalsyndroom en erfelijkheidsonderzoek: psychische reacties in drie generaties van een familie [The long-QT-interval syndrome and hereditary testing: psychic reactions in a three generations family], Ned Tijdschr Geneeskd 2000; 144(21):995-9.
14 Hendriks KSWH, Grosfeld FJM, Wilde AAM, van den Bout J, van Langen IM, van Tintelen JP, ten Kroode HFJ. High distress in parents whose children undergo predictive testing for Long QT syndrome. Com Genet (in press).
15 Dudok de Wit AC, Tibben A, Duivenvoorden HJ, Niemeijer MF, Passchier J. Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? J Med Genet 1998;35:745-54.
16 Grosfeld FJM Lips CJM, Beemer FA, Blijham GH, Mastenbroek MR ten Kroode HFJ. Distress in MEN2 family members and partners prior to DNA test disclosure. Am J Med Genet 2000;91:1 -7.
17 Lodder L, Frets PG,Trijsburg RW, Meijers-Heijboer EJ, Klijn JGM, Duivenvoorden HJ, Tibben A, Wagner A, van der Meer CA, Van den Ouweland AMW, Niermeijer MR Psychological impact of receiving a BRCA1/BRCA2 test result. Am J Med Genet 2001;98:15-24.
18 Kessler S, Field T, Worth L, Mosbarger H. Attitudes of persons at risk for Huntington Disease toward predictive testing. Am J Med Genet 1987;26:259-70.
19 Kessler S. Reinventing the wheel. Am J Med Genet 1993;45:694-5. 20 Dudok de Wit AC, Tibben A, Duivenvoorden HJ, Frets PG, Zoeteweij MW, Losekoot M, van Haeringen A,
150
A N EXTENDED FAMILY WITH A HEREDITARY ARRHYTHMIA
Niermeijer MRPasschier J. Psychological distress in applicants of predicitive DNA testing for autosomal dominant inheritable late onset disorders. J Med Genet 1997:34:382-90.
21 Lerman C, Croyle RT. Genetic testing for cancer predisposition: behavioral science issues. Monogr Natl Cancer Inst 1995:17:63-6.
22 Lodder LN, Frets PG,Trijsburg RW, Meijers-Heijboer EJ, Klijn JGM, Duivenvoorden HJ.Tibben A, Wagner A, van der Meer CA, Devilee P, Cornelisse CJ, van den Ouweland AMW, Halley DJJ, Seynaeve CTilanus MMA, Bartels CCM, Verhoog L.C, Brekelmans CTM, van Geel AN, Dukel L, Dudok de Wit AC, Niermeijer MR Presymptomatic testing for BRCA1 and BRCA2: how distressing are the pre-test weeks? J Med Genet 1999:36:906-13.
23 Watson M, Murday V, Lloyd 5, Ponder B.Averill D, Eeles R. Genetic testing in breast/ovarian cancer (BRCA1) families. Lancet 1995:346:583.
151